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Aziridine synthesis by coupling amines and alkenes via an electrogenerated dication

Nature volume 596, pages 74–79 (2021)Cite this article

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Abstract

Aziridines—three-membered nitrogen-containing cyclic molecules—are important synthetic targets. Their substantial ring strain and resultant proclivity towards ring-opening reactions makes them versatile precursors of diverse amine products1,2,3, and, in some cases, the aziridine functional group itself imbues important biological (for example, anti-tumour) activity4,5,6. Transformation of ubiquitous alkenes into aziridines is an attractive synthetic strategy, but is typically accomplished using electrophilic nitrogen sources rather than widely available amine nucleophiles. Here we show that unactivated alkenes can be electrochemically transformed into a metastable, dicationic intermediate that undergoes aziridination with primary amines under basic conditions. This new approach expands the scope of readily accessible N-alkyl aziridine products relative to those obtained through existing state-of-the-art methods. A key strategic advantage of this approach is that oxidative alkene activation is decoupled from the aziridination step, enabling a wide range of commercially available but oxidatively sensitive7 amines to act as coupling partners for this strain-inducing transformation. More broadly, our work lays the foundations for a diverse array of difunctionalization reactions using this dication pool approach.

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Fig. 1: Development of an oxidative coupling strategy for aziridine synthesis.
Fig. 2: Scope of the aziridination reaction.
Fig. 3: Synthetic applications of the dication pool strategy.
Fig. 4: Mechanistic insight into adduct formation.

Data availability

Crystallographic data for compounds 1 and 2 can be obtained free of charge from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk). All data supporting the findings of this paper are available within the paper and its Supplementary Information.

References

  1. Sweeney, J. B. Aziridines: epoxides’ ugly cousins? Chem. Soc. Rev. 31, 247–258 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Stanković, S. et al. Regioselectivity in the ring opening of non-activated aziridines. Chem. Soc. Rev. 41, 643–665 (2012).

    Article  PubMed  Google Scholar 

  3. Botuha, C., Chemla, F., Ferreira, F. & Pérez‐Luna, A. in Heterocycles in Natural Product Synthesis 1–39 (John Wiley, 2011).

  4. Ismail, F. M. D., Levitsky, D. O. & Dembitsky, V. M. Aziridine alkaloids as potential therapeutic agents. Eur. J. Med. Chem. 44, 3373–3387 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Thibodeaux, C. J., Chang, W. & Liu, H. Enzymatic chemistry of cyclopropane, epoxide, and aziridine biosynthesis. Chem. Rev. 112, 1681–1709 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Lowden, P. A. S. in Aziridines and Epoxides in Organic Synthesis 399–442 (John Wiley, 2006).

  7. Roth, H. G., Romero, N. A. & Nicewicz, D. A. Experimental and calculated electrochemical potentials of common organic molecules for applications to single-electron redox chemistry. Synlett 27, 714–723 (2016).

    CAS  Google Scholar 

  8. Evans, D. A., Faul, M. M. & Bilodeau, M. T. Copper-catalyzed aziridination of olefins by (N-(p-toluenesulfonyl)imino)phenyliodinane. J. Org. Chem. 56, 6744–6746 (1991).

    Article  CAS  Google Scholar 

  9. Sweeney, J. B. in Aziridines and Epoxides in Organic Synthesis 117–144 (John Wiley, 2006).

  10. Osborn, H. M. I. & Sweeney, J. The asymmetric synthesis of aziridines. Tetrahedron Asymmetry 8, 1693–1715 (1997).

    Article  CAS  Google Scholar 

  11. Wang, H., Yang, J. C. & Buchwald, S. L. CuH-catalyzed regioselective intramolecular hydroamination for the synthesis of alkyl-substituted chiral aziridines. J. Am. Chem. Soc. 139, 8428–8431 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Legnani, L., Prina-Cerai, G., Delcaillau, T., Willems, S. & Morandi, B. Efficient access to unprotected primary amines by iron-catalyzed aminochlorination of alkenes. Science 362, 434–439 (2018).

    Article  ADS  CAS  PubMed  Google Scholar 

  13. Jat, J. L. et al. Direct stereospecific synthesis of unprotected N–H and N-Me aziridines from olefins. Science 343, 61–65 (2014).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ma, Z., Zhou, Z. & Kürti, L. Direct and stereospecific synthesis of N–H and N-alkyl aziridines from unactivated olefins using hydroxylamine-O-sulfonic acids. Angew. Chem. Int. Edn 56, 9886–9890 (2017).

    Article  CAS  Google Scholar 

  15. Cheng, Q.-Q. et al. Organocatalytic nitrogen transfer to unactivated olefins via transient oxaziridines. Nat. Catal. 3, 386–392 (2020).

    Article  CAS  Google Scholar 

  16. Falk, E., Makai, S., Delcaillau, T., Gürtler, L. & Morandi, B. Design and scalable synthesis of N-alkylhydroxylamine reagents for the direct iron-catalyzed installation of medicinally relevant amines. Angew. Chem. Int. Edn 59, 21064–21071 (2020).

    Article  CAS  Google Scholar 

  17. Munnuri, S., Anugu, R. R. & Falck, J. R. Cu(II)-mediated N–H and N-alkyl aryl amination and olefin aziridination. Org. Lett. 21, 1926–1929 (2019).

    Article  CAS  PubMed  Google Scholar 

  18. Govaerts, S. et al. Photoinduced olefin diamination with alkylamines. Angew. Chem. Int. Edn 59, 15021–15028 (2020).

    Article  CAS  Google Scholar 

  19. eMolecules (eMolecules Inc, accessed 20 January 2021); https://www.emolecules.com

  20. Lohray, B. B., Gao, Y. & Sharpless, K. B. One pot synthesis of homochiral aziridines and aminoalcohols from homochiral 1,2-cyclic sulfates. Tetrahedr. Lett. 30, 2623–2626 (1989).

    Article  CAS  Google Scholar 

  21. Wenker, H. The preparation of ethylene imine from monoethanolamine. J. Am. Chem. Soc. 57, 2328 (1935).

    Article  CAS  Google Scholar 

  22. Li, X., Chen, N. & Xu, J. An improved and mild Wenker synthesis of aziridines. Synthesis 20, 3423–3428 (2010).

    Google Scholar 

  23. Yan, M., Kawamata, Y. & Baran, P. S. Synthetic organic electrochemical methods since 2000: on the verge of a renaissance. Chem. Rev. 117, 13230–13319 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wiebe, A. et al. Electrifying organic synthesis. Angew. Chem. Int. Edn 57, 5594–5619 (2018).

    Article  CAS  Google Scholar 

  25. Francke, R. & Little, R. D. Redox catalysis in organic electrosynthesis: basic principles and recent developments. Chem. Soc. Rev. 43, 2492–2521 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Moeller, K. D. Using physical organic chemistry to shape the course of electrochemical reactions. Chem. Rev. 118, 4817–4833 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Yoshida, J., Kataoka, K., Horcajada, R. & Nagaki, A. Modern strategies in electroorganic synthesis. Chem. Rev. 108, 2265–2299 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Sauer, G. S. & Lin, S. An electrocatalytic approach to the radical difunctionalization of alkenes. ACS Catal. 8, 5175–5187 (2018).

    Article  CAS  Google Scholar 

  29. Doobary, S., Sedikides, A. T., Caldora, H. P., Poole, D. L. & Lennox, A. J. J. Electrochemical vicinal difluorination of alkenes: scalable and amenable to electron-rich substrates. Angew. Chem. Int. Edn 59, 1155–1160 (2020).

    Article  CAS  Google Scholar 

  30. Siu, T. & Yudin, A. K. Practical olefin aziridination with a broad substrate scope. J. Am. Chem. Soc. 124, 530–531 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Oseka, M. et al. Electrochemical aziridination of internal alkenes with primary amines. Chem 7, 255–266 (2021).

    Article  CAS  Google Scholar 

  32. Chen, J. et al. Electrocatalytic aziridination of alkenes mediated by n-Bu4NI: a radical pathway. Org. Lett. 17, 986–989 (2015).

    Article  CAS  PubMed  Google Scholar 

  33. Li, J. et al. Electrochemical aziridination by alkene activation using a sulfamate as the nitrogen source. Angew. Chem. Int. Edn 57, 5695–5698 (2018).

    Article  CAS  Google Scholar 

  34. Yoshida, J., Shimizu, A. & Hayashi, R. Electrogenerated cationic reactive intermediates: the pool method and further advances. Chem. Rev. 118, 4702–4730 (2018).

    Article  CAS  PubMed  Google Scholar 

  35. Hayashi, R., Shimizu, A. & Yoshida, J. The stabilized cation pool method: metal- and oxidant-free benzylic C–H/aromatic C–H cross-coupling. J. Am. Chem. Soc. 138, 8400–8403 (2016).

    Article  CAS  PubMed  Google Scholar 

  36. Shine, H. J., Bandlish, B. K., Mani, S. R. & Padilla, A. G. Ion radicals. 43. Addition of thianthrene and phenoxathiin cation radicals to alkenes and alkynes. J. Org. Chem. 44, 915–917 (1979).

    Article  CAS  Google Scholar 

  37. Shine, H. J. et al. Adducts of phenoxathiin and thianthrene cation radicals with alkenes and cycloalkenes. J. Org. Chem. 68, 8910–8917 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Rangappa, P. & Shine, H. J. An overview of some reactions of thianthrene cation radical. Products and mechanisms of their formation. J. Sulfur Chem. 27, 617–664 (2006).

    Article  CAS  Google Scholar 

  39. Berger, F. et al. Site-selective and versatile aromatic C−H functionalization by thianthrenation. Nature 567, 223–228 (2019).

    Article  ADS  CAS  PubMed  Google Scholar 

  40. Engl, P. S. et al. C–N cross-couplings for site-selective late-stage diversification via aryl sulfonium salts. J. Am. Chem. Soc. 141, 13346–13351 (2019).

    Article  CAS  PubMed  Google Scholar 

  41. Chen, J., Li, J., Plutschack, M. B., Berger, F. & Ritter, T. Regio- and stereoselective thianthrenation of olefins to access versatile alkenyl electrophiles. Angew. Chem. Int. Edn 59, 5616–5620 (2020).

    Article  CAS  Google Scholar 

  42. Houmam, A., Shukla, D., Kraatz, H.-B. & Wayner, D. D. M. Electrosynthesis of mono- and bisthianthrenium salts. J. Org. Chem. 64, 3342–3345 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Iwai, K. & Shine, H. J. Ion radicals. 46. Reactions of the adducts of thianthrene and phenoxathiin cation radicals and cyclohexene with nucleophiles. J. Org. Chem. 46, 271–276 (1981).

    Article  CAS  Google Scholar 

  44. Mitchell, S. C. & Waring, R. H. Fate of thianthrene in biological systems. Xenobiotica 47, 731–740 (2017).

    Article  CAS  PubMed  Google Scholar 

  45. Kaiser, D., Klose, I., Oost, R., Neuhaus, J. & Maulide, N. Bond-forming and -breaking reactions at sulfur(IV): sulfoxides, sulfonium salts, sulfur ylides, and sulfinate salts. Chem. Rev. 119, 8701–8780 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bright, G. M., Brodney, M. A. & Wlodecki, B. Pyridyloxymethyl and benzisoxazole azabicyclic derivatives. International patent WO/2004/081007 (2004).

  47. Qian, D.-Q., Shine, H. J., Guzman-Jimenez, I. Y., Thurston, J. H. & Whitmire, K. H. Mono- and bisadducts from the addition of thianthrene cation radical salts to cycloalkenes and alkenes. J. Org. Chem. 67, 4030–4039 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Speer, M. E. et al. Thianthrene-functionalized polynorbornenes as high-voltage materials for organic cathode-based dual-ion batteries. Chem. Commun. 51, 15261–15264 (2015).

    Article  CAS  Google Scholar 

  49. Murata, Y. & Shine, H. J. Ion radicals. XVIII. Reactions of thianthrenium perchlorate and thianthrenium trichlorodiiodide. J. Org. Chem. 34, 3368–3372 (1969).

    Article  CAS  Google Scholar 

  50. Sandford, C. et al. A synthetic chemist’s guide to electroanalytical tools for studying reaction mechanisms. Chem. Sci. 10, 6404–6422 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank A. Wendlandt, M. Levin and. D. Weix for suggestions and manuscript proofreading. We also acknowledge A. Hoque and F. Wang in the Stahl laboratory for the use of, and technical assistance with, the electrochemical flow reactor. Additionally, we thank the Weix, Stahl, Yoon and Schomaker groups for sharing their chemical inventories. B. J. Thompson is acknowledged for his assistance with the design and fabrication of the power supply. T. Drier is acknowledged for the fabrication of electrochemical glassware. A. M. Wheaton is acknowledged for assistance with crystallographic studies. We also acknowledge support and suggestions from all members of the Wickens group throughout the investigation of this project. This work was supported financially by the Office of the Vice Chancellor for Research and Graduate Education at the University of Wisconsin–Madison, with funding from the Wisconsin Alumni Research Foundation. Spectroscopic instrumentation was supported by a gift from P. J. and M. M. Bender, by National Science Foundation (NSF) grant CHE-1048642, and by National Institutes of Health (NIH) grants 1S10OD020022-1 and S10 OD01225. This study also made use of the National Magnetic Resonance Facility at Madison, which is supported by NIH grants P41GM136463 (old number P41GM103399 (NIGMS)) and P41RR002301. Equipment was purchased with funds from the University of Wisconsin–Madison, the NIH (grants P41GM103399, S10RR02781, S10RR08438, S10RR023438, S10RR025062 and S10RR029220), the NSF (DMB-8415048, OIA-9977486 and BIR-9214394), and the US Department of Agriculture (USDA). The Bruker D8 VENTURE Photon III X-ray diffractometer was partially funded by NSF award CHE-1919350 to the University of Wisconsin–Madison Department of Chemistry.

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  1. These authors contributed equally: Dylan E. Holst, Diana J. Wang

Authors and Affiliations

  1. Department of Chemistry, University of Wisconsin–Madison, Madison, WI, USA

    Dylan E. Holst, Diana J. Wang, Min Ji Kim, Ilia A. Guzei & Zachary K. Wickens

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Contributions

Z.K.W., D.E.H. and D.J.W. designed the project. D.E.H., D.J.W. and M.J.K. performed the experiments and collected the data. I.A.G. collected and analysed X-ray data to provide crystal structures. Z.K.W., D.E.H., D.J.W. and M.J.K. analysed the data and contributed to writing the manuscript. D.E.H. and D.J.W. contributed equally.

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Correspondence to Zachary K. Wickens.

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Peer review information Nature thanks Louis-Charles Campeau and David Hickey for their contribution to the peer review of this work. Peer reviewer reports are available.

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Supplementary information

Supplementary Information

The file contains the following sections: 1. General Methods and Materials; 2. Supplementary Data; 3. Mechanistic Investigations; 4. Substrate preparation; 5. General Experimental Procedures; 6. Aziridine Product Isolation and Characterization; 7. Scale-Up Flow Electrolysis Set-Up and Procedure; 8. Aziridine Derivatization Reaction Isolation and Characterization; 9. X-Ray Diffraction Data; 10. References; and 11. NMR Spectra.

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Holst, D.E., Wang, D.J., Kim, M.J. et al. Aziridine synthesis by coupling amines and alkenes via an electrogenerated dication. Nature 596, 74–79 (2021). https://doi.org/10.1038/s41586-021-03717-7

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